text: Early investigations of macrocyclic stereocontrol studied the alkylation of 8-membered cyclic ketones with varying substitution. In the example below, alkylation of 2-methylcyclooctanone occurred to yield the predominantly trans product. Proceeding from the lowest energy conformation of 2-methylcycloctanone, peripheral attack is observed from either one of the low energy (energetic difference of 0.5 (kcal/mol)) enolate conformations, resulting in a trans product from either of the two depicted transition state conformations.
  Unlike the cyclooctanone case, alkylation of 2-cyclodecanone rings does not display significant diastereoselectivity.
  However, 10-membered cyclic lactones display significant diastereoselectivity. The proximity of the methyl group to the ester linkage was directly correlated with the diastereomeric ratio of the reaction products, with placement at the 9 position (below) yielding the highest selectivity. In contrast, when the methyl group was placed at the 7 position, a 1:1 mixture of diastereomers was obtained. Placement of the methyl group at the 9-position in the axial position yields the most stable  ground state conformation of the 10-membered ring leading to high diastereoselectivity.
  Conjugate addition to the E-enone below also follows the expected peripheral attack model to yield predominantly trans product. High selectivity in this addition can be attributed to the placement of sp centers such that transannular nonbonded interactions are minimized, while also placing the methyl substitution in the more energetically favorable position for cyclodecane rings.  This ground state conformation heavily biases conjugate addition to the less hindered diastereoface.